Aging cells undergo several modifications associated with diseased conditions. Hyperglycemia, caused by diabetes mellitus (DM), and oxidative stress promote post-translational modifications of membrane proteins of cells by advanced glycation end-products (AGE). Lindsey J B, et al., “Receptor For Advanced Glycation End-Products (RAGE) and soluble RAGE (sRAGE): Cardiovascular Implications,” Diabetes Vascular Disease Research, Vol. 6(1), 7-14, (2009) at p. 8. AGE arise from a nonenzymatic reaction of sugars with protein side-chains in aging cells and is involved in the pathogenesis of several age-related disease processes, including adverse complications of diabetes. Ando K, et al., “Membrane Proteins of Human Erythrocytes Are Modified by Advanced Glycation End Products During Aging in the Circulation,” Biochemical and Biophysical Research Communications, Vol. 258, 123-27 (1999) at p. 123.
AGE-modified erythrocytes have less flexibility than non-modified erythrocytes, and have been implicated in the pathogenesis of atherosclerosis, while the absence of AGE-modified erythrocytes has been correlated with reduced atherosclerosis. Jandeleit-Dahm K, et al., “The AGE/RAGE Axis in Diabetes-Accelerated Atherosclerosis,” Clinical and Experimental Pharmacology and Physiology, Vol. 35, 329-334 (2008) at 330. Localization of AGEs in atherosclerotic lesions of the aorta in non-diabetic patients has been reported in intima cells, endothelial cells, smooth muscle cells, macrophages and foam cells. Sakata N. et al., “Immunohistochemical Localization of Different Epitopes of Advanced Glycation End Products in Human Atherosclerotic Lesions,” Atherosclerosis, 141, 61-75 (1998) at p. 71. The damage caused by AGE-modified cells may also lead to nephropathy, retinopathy, neuropathy, heart disease, stroke, and peripheral vascular disease. Karachalias N. et al., “Accumulation of Fructosyl-Lysine and Advanced Glycation End Products in the Kidney, Retina and Peripheral Nerve of Streptozotocin-Induced Diabetic Rats.” Biochemical Society Transactions, 31, 1423-25 (2003) at 1423.